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Your search keyword '"Ferdek, Pawel E"' showing total 5 results
Start Over Author "Ferdek, Pawel E" Publisher wiley
5 results on '"Ferdek, Pawel E"'

2. ABT‐199 (Venetoclax), a BH3‐mimetic Bcl‐2 inhibitor, does not cause Ca2+‐signalling dysregulation or toxicity in pancreatic acinar cells

Author

Jakubowska, Monika A, primary, Kerkhofs, Martijn, additional, Martines, Claudio, additional, Efremov, Dimitar G, additional, Gerasimenko, Julia V, additional, Gerasimenko, Oleg V, additional, Petersen, Ole H, additional, Bultynck, Geert, additional, Vervliet, Tim, additional, and Ferdek, Pawel E, additional

Published
2018
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3. Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium-driven bile uptake

Author

Ferdek, Pawel E., Jakubowska, Monika A., Gerasimenko, Julia V., Gerasimenko, Oleg V., and Petersen, Ole H.

Subjects
Q1, digestive system
Abstract

Acute biliary pancreatitis, caused by bile reflux into the pancreas, is a serious condition characterised by premature activation of digestive enzymes within acinar cells, followed by necrosis and inflammation. Bile acids are known to induce pathological Ca2+ signals and necrosis in acinar cells. However, bile acid-elicited signalling events in stellate cells remain unexplored. This is the first study to demonstrate the pathophysiological effects of bile acids on stellate cells in two experimental models: ex vivo (mouse pancreatic lobules) and in vitro (human cells). Sodium cholate and taurocholate induced cytosolic Ca2+ elevations in stellate cells, larger than those elicited simultaneously in the neighbouring acinar cells. In contrast, taurolithocholic acid 3-sulfate (TLC-S), known to induce Ca2+ oscillations in acinar cells, had only minor effects on stellate cells in lobules. The dependence of the Ca2+ signals on extracellular Na+ and the presence of sodium-taurocholate cotransporting polypeptide (NTCP) indicate a Na+-dependent bile acid uptake mechanism in stellate cells. Bile acid treatment caused necrosis predominantly in stellate cells, which was abolished by removal of extracellular Ca2+ and significantly reduced in the absence of Na+, showing that bile-dependent cell death was a downstream event of Ca2+ signals. Finally, combined application of TLC-S and the inflammatory mediator bradykinin caused more extensive necrosis in both stellate and acinar cells than TLC-S alone. Our findings shed new light on the mechanism by which bile acids promote pancreatic pathology. This involves not only signalling in acinar cells but also in stellate cells.

Published
2016

5. ABT-199 (Venetoclax), a BH3-mimetic Bcl-2 inhibitor, does not cause Ca 2+ -signalling dysregulation or toxicity in pancreatic acinar cells.

Author

Jakubowska MA, Kerkhofs M, Martines C, Efremov DG, Gerasimenko JV, Gerasimenko OV, Petersen OH, Bultynck G, Vervliet T, and Ferdek PE

Subjects
Acinar Cells metabolism, Animals, Male, Mice, Inbred C57BL, Pancreas cytology, Peptide Fragments, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Acinar Cells drug effects, Antineoplastic Agents pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Calcium Signaling drug effects, Sulfonamides pharmacology
Abstract

Background and Purpose: Many cancer cells depend on anti-apoptotic B-cell lymphoma 2 (Bcl-2) proteins for their survival. Bcl-2 antagonism through Bcl-2 homology 3 (BH3) mimetics has emerged as a novel anti-cancer therapy. ABT-199 (Venetoclax), a recently developed BH3 mimetic that selectively inhibits Bcl-2, was introduced into the clinic for treatment of relapsed chronic lymphocytic leukaemia. Early generations of Bcl-2 inhibitors evoked sustained Ca 2+ responses in pancreatic acinar cells (PACs) inducing cell death. Therefore, BH3 mimetics could potentially be toxic for the pancreas when used to treat cancer. Although ABT-199 was shown to kill Bcl-2-dependent cancer cells without affecting intracellular Ca 2+ signalling, its effects on PACs have not yet been determined. Hence, it is essential and timely to assess whether this recently approved anti-leukaemic drug might potentially have pancreatotoxic effects., Experimental Approach: Single-cell Ca 2+ measurements and cell death analysis were performed on isolated mouse PACs., Key Results: Inhibition of Bcl-2 via ABT-199 did not elicit intracellular Ca 2+ signalling on its own or potentiate Ca 2+ signalling induced by physiological/pathophysiological stimuli in PACs. Although ABT-199 did not affect cell death in PACs, under conditions that killed ABT-199-sensitive cancer cells, cytosolic Ca 2+ extrusion was slightly enhanced in the presence of ABT-199. In contrast, inhibition of Bcl-xL potentiated pathophysiological Ca 2+ responses in PACs, without exacerbating cell death., Conclusion and Implications: Our results demonstrate that apart from having a modest effect on cytosolic Ca 2+ extrusion, ABT-199 does not substantially alter intracellular Ca 2+ homeostasis in normal PACs and should be safe for the pancreas during cancer treatment., Linked Articles: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc., (© 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Published
2019
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